3,5-Diiodo-L-thyronine (3,5-T2) vs SLU-PP-915

Metabolic

Metabolic

Research Only

Research Only

3,5-T2 acts largely independently of classical nuclear thyroid hormone receptor (THRβ) genomic signaling, with substantially lower THRβ affinity than T3. The primary mechanism is direct, non-genomic action at mitochondria: 3,5-T2 binds cytochrome-c oxidase subunit Va and abolishes the allosteric inhibition of respiration by ATP, rapidly increasing oxygen consumption. In rodent studies, it activates the AMPK–ACC–malonyl-CoA signaling pathway, increasing mitochondrial fatty-acid oxidation and redirecting lipid partitioning toward oxidation.

The estrogen-related receptors (ERRα/β/γ) are orphan nuclear receptors that act as master transcriptional regulators of oxidative metabolism, driving mitochondrial biogenesis, oxidative phosphorylation, fatty-acid oxidation, and the TCA cycle — largely as partners of the PGC-1 coactivators. SLU-PP-915 binds and activates all three ERR isoforms with an EC50 of roughly 400 nM at each. In its medicinal-chemistry design, the phenol and aniline groups of earlier ERR agonists were replaced with a boronic-acid moiety on a disubstituted thiophene scaffold, which preserved receptor activity while improving microsomal metabolic stability and oral exposure. In cells and in rodents it upregulates canonical ERR target genes including PGC-1α, lactate dehydrogenase A (LDHA), pyruvate dehydrogenase kinase 4 (PDK4), and DNA-damage-inducible transcript 4 (DDIT4).

Not established in humans; engineered for improved metabolic stability and oral exposure relative to first-generation ERR agonists